Optimizing the diagnostic yield of invasive coronary function testing

Traditionally, the management of patients with angina pectoris or angina-equivalent symptoms is mainly concentrated on the presence of obstructive coronary artery disease (CAD). However, approximately 50% of patients undergoing invasive coronary angiography have no evidence of hemodynamically significant epicardial CAD as assessed by visual estimation or invasive pressure measurements (1). In 60–90% of patients with angina and nonobstructive coronary arteries (ANOCA), coronary vasomotor dysfunction (CVDys) can be identified as the underlying pathophysiology (2,3). In patients with CVDys, angina pectoris or myocardial ischemia is the result of a relative mismatch between coronary artery blood flow and oxygen demand due to an impaired function of the coronary macro- and/or microcirculation. CVDys comprises coronary endothelial dysfunction, coronary (epicardial and microvascular) artery spasm (CAS), and coronary microvascular dysfunction (CMD) (4). CVDys is associated with a high burden of anginal symptoms, frequent hospitalizations and re-catheterization, a reduced quality of life, and an increased risk for adverse cardiovascular events (5,6). Early identification of the different endotypes of CVDys, and targeted pharmacological treatment is essential to improve quality of life and reduce the risk of adverse cardiac events in ANOCA patients (5).

Comprehensive invasive coronary function testing (CFT) can establish the diagnosis of CVDys and specify the endotypes in ANOCA patients. After coronary angiography is performed to rule out obstructive CAD with certainty, intracoronary pharmacological stimuli are administrated to document potential endothelial dysfunction and/or CAS. Various pharmacological stimuli are available for coronary vasoreactivity testing, however, the most widely used in clinical practice are acetylcholine (ACh) and ergonovine (ER). The effect of ACh and ER on the coronary artery vasomotor function differs. Administration of ACh in healthy coronary arteries results in: (I) a release of several endothelium-dependent relaxation factors (mainly nitric oxide) from the coronary endothelium, and (II) vasoconstriction of vascular smooth muscle cells (VSMC) that is attenuated or even reversed by the vasodilator effect of healthy endothelium. Hence, in healthy individuals, ACh has a net vasodilating effect, but a potent vasoconstrictive effect in individuals with endothelial dysfunction or hyperreactive VSMC. Administration of ER, however, directly affects the VSMC of healthy coronary arteries by activation of serotonergic (5-HT2) receptors initiating vasoconstriction. While ACh can only be administered directly into the coronary artery due to its short half-life, ER can be administered intravenously. However, the latter may result in a prolonged simultaneous vasospasm of both the left coronary artery (LCA) and/or right coronary artery (RCA) which may be difficult to reverse without intracoronary injection of nitroglycerine (NTG).

During CFT, intracoronary administration of low-dose ACh (up to 100 µg) allows assessment of endothelium-dependent vasodilatation by measuring the coronary blood flow (CBF) response or the change in diameter of the coronary artery. Coronary endothelial dysfunction, characterized by a blunted ACh-mediated vasodilator response, is defined as any reduction of the epicardial coronary diameter and/or <50% increase in CBF volume in response to low-dose ACh compared with baseline. Severe endothelial dysfunction, most strongly associated with adverse events, is defined as a reduction of ≥20% of the epicardial coronary diameter and/or a reduction of <50% in CBF (7). Of note, assessment of coronary endothelial dysfunction may be limited as some patients may have epicardial coronary spasm after administration of low-dose ACh. In particular, female patients showed a significantly higher grade of epicardial coronary spasm at 2 or 20 µg Ach compared with male patients (female 10% vs. male 2%) (8). Intracoronary administration of high-dose ACh (100 or 200 µg) or intravenous ER allows assessment of CAS. Epicardial coronary spasm is defined according to the definition used by the Coronary Vasomotor Disorders International Study Group (COVADIS) and requires all of the following: (I) reproduction of previously reported chest pain, (II) induction of ischemic ECG changes, and (III) >90% epicardial vasoconstriction by visual estimation (9). Microvascular coronary spasm is defined when the first 2 diagnostic criteria are met, but in the absence of epicardial vasoconstriction of >90% (10).

The coexistence of epicardial and microvascular coronary spasm has been reported. Compared to epicardial coronary spasm, patients with microvascular coronary spasm have a high symptom burden despite medical treatment and the efficacy of nitrates is poor when compared to epicardial coronary spasm. Rechallenging the coronary arteries with intracoronary ACh (“ACh rechallenge”) immediately after intracoronary NTG administration can detect coexisting epicardial coronary spasm and microvascular coronary spasm and, subsequently, allows assessment of the efficacy of treatment with nitrates to prevent re-occurrence of spasm in an individual patient (11). Seitz et al. showed that using the ACh rechallenge method, NTG administration prevented microvascular coronary spasm in 20% of the patients and attenuated microvascular coronary spasm in 49%. Hence, a subset of patients with microvascular coronary spasm may still benefit from nitrates or an alternative nitric oxide-based therapy such as nicorandil or molsidomine (11).

CMD relates to the inability of the coronary microcirculation to dilate adequately in response to an increase in myocardial demand. Intracoronary administration of adenosine allows assessment of endothelium-independent vasodilator reserve capacity of the coronary microcirculation and can be performed by either thermodilution or Doppler flow velocity. When using thermodilution, repeated 3 mL intracoronary saline bolus both in rest and during hyperemia, induced by intravenous adenosine 140 µg/kg/min, are performed to measure the various indices with the use of a guidewire with pressure and temperature sensors in the distal part of the coronary artery (PressureWire X, Abbott Vascular, Santa Clara, CA, USA). Calculations require the use of dedicated software (Coroventis Coroflow, Uppsala, Sweden). Coronary flow reserve (CFR) is the ratio between hyperemic mean transit time (Tmn_hyp) and resting mean transit time (Tmn_rest) of the bolus saline in a coronary artery. The index of microvascular resistance (IMR) is calculated by multiplying mean distal aortic pressure (Pd) with mean Tmn_hyp. IMR_corr corrects for epicardial collateral flow contribution (IMR_corr = Pa × Tmn × [(1.35 × Pd/Pa) − 0.32] (10). When using Doppler flow velocity measurements, a Doppler flow velocity tipped sensor guidewire (ComboWire or FloWire; Philips Volcano, San Diego, CA, USA) as well as a dedicated device (ComboMap; Philips Volcano) and software are needed. CFR is the ratio between hyperemic and resting averaged peak Doppler flow velocity (APV). Doppler flow velocity-derived hyperemic microvascular resistance (HMR) is defined as the ratio of (drift-corrected) distal coronary pressure to APV in hyperemic conditions (12,13). CMD, i.e. an impaired vasodilatory capacity, characterized by a reduced adenosine-mediated response, is defined as an abnormal CFR (<2.5) and/or an IMR ≥25 (as assessed by thermodilution) or HMR ≥2.5 mmHg/cm/s (as assessed by Doppler flow velocity).

Within one patient multiple endotypes of CVDys can be present and therefore targeted treatment can be challenging. For instance, CMD can be treated with beta-blockers while this is contraindicated in epicardial coronary spasm as beta-blockers may luxate spasm. Feenstra et al. evaluated the presence of concomitant endotypes and showed that 17% of patients with ischemia but with nonobstructive CAD on coronary angiography (INOCA) had CAS and CMD (4). Moreover, coronary endothelial dysfunction was present in the vast majority of INOCA patients with CAS and/or CMD. In patient with no inducible CAS and a normal vasodilatory capacity, 68% had coronary endothelial dysfunction of which 37% had severe endothelial dysfunction.

The guidelines from the American College of Cardiology/American Heart Association (1), European Society of Cardiology (14), and Japanese Circulation Society (15) emphasise that CFT should be applied in routine clinical practice in patients with ANOCA. Despite the potential benefits, the adoption of CFT in daily practice remains limited and a large variety of CFT protocols exists even between ANOCA expert centers. There are several important practical considerations to take into account when performing CFT that may affect the diagnostic yield for diagnosing CVDys in patients with ANOCA (16). Noteworthy, ACh has a very short half-life and testing for coronary vasoreactivity requires intracoronary bolus injection of high-dose ACh (up to 200 µg for the LCA and 80 µg for the RCA) in 20 seconds to reach a sufficient intracoronary concentration of ACh in an effort to provoke spasm. Several studies have shown that increasing the maximal dose of ACh from 100 to 200 µg in the LCA and from 50 to 80 µg in the RCA, injected in 20 seconds, will increase the number of positive tests for CAS and multivessel spasm will be diagnosed more frequently (17,18). Some protocols have suggested bolus injection in 1 minute or a maximum 100 µg ACh in the LCA which inevitably will result in a lower intracoronary concentration of ACh and consequently a lower diagnostic yield. Moreover, testing coronary vasoreactivity function of the LCA is directly influenced by the position of the guiding catheter through which ACh reaches the coronary artery. Most CFT protocols advocate positioning the guiding catheter in the left main (thereby testing the complete LCA) allowing identification of multivessel spasm. In contrast, other CFT protocols selectively test the left anterior descending artery (LAD), by placing a 2.2-Fr tracker coronary infusion catheter (SCIMED Life Systems/Boston Scientific) into the proximal LAD, to prevent the occurrence of multivessel or left main spasm. Differences in time, dosages and guiding catheter position may affect sensitivity and specificity of the CFT to some extent. Validation studies of CFT have demonstrated a high sensitivity and specificity for both the ACh (90% and 99%, respectively) and ER (91 and 97%, respectively) protocols for the diagnosis of coronary vasoconstriction in ANOCA patients (19,20).

The order in which CAS (epicardial and/or microvascular) and CMD should be tested is under debate. Testing CMD necessitates intracoronary administration of NTG but this may impede testing coronary vasoreactivity function. Contrarily, whether residual spasm after coronary vasoreactivity testing hampers testing for CMD remains to be determined, particularly in patients who are poor NTG responders such as in the majority of patients with microvascular coronary spasm. CFT can be performed ad hoc after routine diagnostic coronary angiography (CAG), however, when intracoronary physiology needs to be performed to rule out obstructive CAD, intracoronary NTG administration is necessary, potentially interfering with coronary vasomotor testing. Radial artery spasm prophylaxis can be administered as it does not significantly affect coronary vasomotor responses to Ach (21).

In the recent issue of the Journal of the American College of Cardiology: Cardiovascular Interventions, Rehan et al. evaluate the diagnostic yield of single vessel versus multivessel CFT in patients with ANOCA, a critical but understudied aspect of CFT to date (22). In this multicenter study, a total of 80 ANOCA patients (228 vessels) underwent coronary reactivity testing with ACh followed by adenosine-mediated coronary physiology assessment in all 3 major epicardial arteries. A temporary pacing wire was inserted via the femoral vein to compensate for potential bradycardia. Assessment of the LCA was performed via incremental doses of 20, 50, 100, and 200 µg of ACh injected over 20 seconds, and of the RCA with incremental doses of 20, 50, and 80 µg, with a 2-minute interval between doses (in 96.3% of patients the LCA was tested first). If CAS was induced together with recognizable symptoms and ischemic ECG changes, the provocation test was considered to be positive and the test was then terminated. After a 10-minute interval, adenosine-mediated coronary physiology was performed using bolus thermodilution to evaluate the presence of CMD. Measurements in small, nondominant, or severely tortuous coronary arteries were avoided for safety reasons. The main findings of the study are: (I) compared with single vessel, multivessel CFT showed a significantly greater prevalence of CVDys (86.3% vs. 68.8%; P=0.0005), CAS (60.0% vs. 47.5%; P=0.004), and CMD (62.5% vs. 37.5%; P<0.001); (II) CAS was predominantly observed in the LCA but isolated RCA spasm was present in 20.8%; (III) 40% had 1-vessel CAS and 20.3% had multivessel CAS with the majority of patients having epicardial spasm; (IV) 33.8% had 1-vessel CMD and 28.8% had multivessel CMD; and (V) multivessel CFT altered the final diagnosis in 33.8% of ANOCA-patients.

Rehan et al. are to be complimented as they raise an important issue regarding the diagnostic yield of CFT of ANOCA patients (22). To establish the diagnosis of CVDys in ANOCA-patients, CFT should not be limited to measurements in one coronary artery. The distribution of the underlying pathophysiology leading to CAS and CMD is assumingly not homogenous in the coronary arteries and, therefore, multivessel coronary vasoreactivity testing and adenosine-mediated coronary physiology assessment is important. Most ANOCA expert centers start coronary vasoreactivity testing by in the LCA and when found negative, the RCA is usually tested with a single dose ACh of 50 or 80 µg (16). Particularly, ACh provocation testing in the RCA in 20 seconds may cause extensive bradyarrhythmia, for which temporary pacemaker wire insertion may be considered or adjustment of the infusion time to 1 minute. When CAS is diagnosed in the LCA, testing of the RCA is still relevant for assessment of prognosis. Hence, a large registry including 2,960 ANOCA-patients, showed that multivessel CAS was associated with a worse clinical outcome compared to single vessel CAS (23). In this study the composite of cardiac death, acute coronary syndrome, and symptomatic new onset arrhythmia was significantly higher in the multivessel CAS group (n=104) than in the single vessel CAS (n=163) and non-CAS groups (n=737) (8.7% vs. 1.8% and 1.1%, each log-rank P<0.05, respectively) over a 36-month follow-up period. Multivessel CAS was an independent predictor of the composite endpoint at 36 months (hazard ratio 8.5, 95% CI: 2.6–27.2, P<0.0001). In addition, in the comprehensive clinical risk score developed by the Japanese Coronary Spasm Association (JCSA), the so-called JCSA risk score, multivessel spasm is a contributing risk factor besides history of out of-hospital cardiac arrest (4 points), smoking, angina at rest alone, organic coronary stenosis, multivessel spasm (2 points each), ST-segment elevation during angina, and beta-blocker use (1 point each) (24). According to the total score in individual patients, a low risk (score 0 to 2), an intermediate risk (score 3 to 5), and a high risk (score 6 or more) strata were defined corresponding with increasing incidences of major adverse cardiovascular events (MACE) (2.5%, 7.0%, and 13.0%, respectively; P<0.001).

Regarding CMD, Rehan et al. found that multivessel testing significantly increased the diagnostic yield, however, vessel-specific analysis showed that this was mainly due to the increased detection of isolated microvascular resistance as measured by IMR (22). A numerical higher prevalence of an abnormal IMR was observed in the left circumflex coronary artery (LCx) (77.8%) and RCA (76.0%) compared with the LAD (62.1%), (P=0.361). IMR is dependent on the extent of the perfused myocardial area, where smaller myocardial beds such as the LCx or RCA will lead to a higher prevalence of CMD compared to the LAD (25). In contrast, no significant difference was observed in the presence of abnormal CFR across vessels (P=0.706).

A comprehensive CFT, evaluating all endotypes including multivessel testing and ACh rechallenge enhances the diagnostic yield of CVDys in patients with ANOCA. This approach facilitates a more precise classification of CVDys endotypes and may optimize the pharmacological strategy in this heterogeneous patient population. Future studies are required to improve pharmacological treatment, especially in patients with mixed endotypes, and to elucidate the prognostic implications of multivessel testing for CAS and CMD.

Acknowledgments

None.

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